Rearrangement and cyclisation reactions on the 1-arylpyrrol-2-iminyl – 2-aryliminopyrrol-1-yl radical energy surface

Independent generation of the iminyl (X = N) and pyrrol-1-yl (X = N) radicals by flash vacuum pyrolysis of the corresponding oxime ether and N -(dimethylamino) compound, respectively, provides two regioisomeric pyrrolo1,2-a]quinoxalines compounds. This shows that the radical species interconvert via the spirodienyl moeity at high temperatures. Corresponding generation of the pyrrol-1-yl (X = CH) radical gives the pyrrolo[1,2-a ]quinoline as the only cyclised product. In this case, DFT calculations suggest that direct cyclisation of the pyrrol-1-yl takes place, rather than formation of the spirodienyl species and exclusive migration of the C-N bond


Introduction
In previous papers we have explored the cyclisation reactions of iminyl radicals, generated in the gas-phase under flash vacuum pyrolysis (FVP) conditions. 1 In some cases, e.g.aryliminoiminyls, these reactions are dominated by ipso-attack and rearrangement via spirodienyl radicals (Scheme 1, X = N), 2 leading to mixtures of cyclisation products.The mechanism was supported by 15 N-labelling experiments. 3However, corresponding rearrangements are not observed for arylvinyliminyls 4 (Scheme 1, X = CH), so the products must be formed either by direct cyclisation or by formation of the spirodienyl intermediate followed by exclusive migration of the C-N bond.

Scheme 1. Radical cyclizations forming quinoxalines.
The aims of the work reported here are summarised in Scheme 2. First, we hoped to generate the iminyl 1 (X = N) by the standard method involving FVP of the corresponding oxime ether.With two fused 5-membered rings, the spirodienyl intermediate 3 (X = N) is necessarily more strained than its analogue in Scheme 1 but, if rearrangement were to take place, generation of the pyrrol-1-yl radical 2 (X = N) would provide complementary entry to the energy surface.However, almost nothing is known about the synthetic organic chemistry of pyrrol-1-yl radicals except that a dimeric product is obtained when a vast excess of pyrrole is decomposed in the presence of t-butyl peroxide. 5Tetraarylpyrrol-1-yl radicals have been characterised by EPR spectroscopy, 6 and more recently the pyrrol-1-yl radical itself has been implicated in UV photodissociation experiments 7 and its electron affinity has been measured. 8[10][11][12][13] In the context of the present work, inventing a general FVP precursor to pyrrol-1-yl radicals for use in synthetic and mechanistic chemistry was therefore a major target.With a precursor for 2 (X = N) in place, the strategy was extended to the case of the 2-styrylpyrrolyl 2 (X = CH), though no attempt was made to create a route to the vinyl radical (1, X = CH).Finally, the mechanistic details of the rearrangement processes were analysed by DFT calculations at the B3LYP/cc-pVDZ level.
aminyl and phenoxyl radicals (Scheme 4). 1 The temperature profile of the 910 conversion (Figure 1) shows that temperatures of 800-850 °C are required to complete the homolysis.Accordingly, a precursor to 2 (X = N) was made, in two steps.First, formylation of 9 was carried out by the literature method; 16 the 2-formyl isomer 11 was isolated as the major product (52%) after chromatography, though some of the 3-formyl product 14 was also obtained (12%).The imine 12 (97%) was synthesised by condensation with p-toluidine (Scheme 5).The precursor to 2 (X = CH) was made by Wittig reaction 16 of the aldehyde 11 with the corresponding ylide which gave the 2-styryl compound 13 (Scheme 5).The corresponding 3-styryl compound 15 was made similarly by reaction of the 3-formylpyrrole 14.Only the trans isomers were detected in solution by nmr ( 3 J, 16Hz) FVP of the oxime ether 8 gave two heterocyclic products in essentially equal amounts (40% and 41% isolated yields), together with small amounts of 1-p-tolylpyrrole-2carbonitrile 18 (8%) and 1-p-tolylpyrrole 6 (5%), all of which were separated by chromatography (Scheme 6).The heterocyclic products were identified as 7-methylpyrrolo [1,2-a]  The formation and unambiguous characterisation of 16 and 17 suggests that the iminyl 1 (X = N) is able to undergo ipso-attack to generate the spirodienyl radical 3 (X = N) (Scheme 2) which subsequently rearranges to the two regioisomeric products.However, it is unclear whether interconversion via the spirodienyl is complete or whether this reaction mode competes with direct cyclisation at the ortho-position.Scheme 7. Products of FVP of the dimethylaminopyrrole 12. Reagents and conditions: (i) FVP, 800 °C.More information on this point was gained by FVP of the N-dimethylaminopyrrole 12 at 800 °C (Scheme 7) which provided the two methylpyrrolo[1,2-a]quinoxalines 16 (23% of the mixture) and 17 (73% of the mixture) (4% of mixture not assigned).First, this provides further evidence that the pyrrol-1-yl radical 2 (X = N) can be generated by this route and that it is capable of cyclisation reactions to provide 6-membered ring products.Second, the formation of the two heterocyclic products 16 and 17 shows that at least some cyclisation via the spirodienyl must take place.However, the fact that these products were obtained in unequal ratio (in contrast to the result from FVP of 8) is evidence that direct cyclisation must also play a part in the energy surface summarised by Scheme 2 (see later discussion) and provides the major product from the pyrrol-1-yl.
In contrast, FVP of the styryl compound 13 at 750 °C gave only 8-methylpyrrolo[1,2-a]quinoline 19 (50% yield) (Scheme 8).NOESY analysis confirmed the structure by correlation of a pyrrole proton with a 'singlet' benzenoid proton (c.f.17 in Figure 2).In this case E/Z-isomerisation of the alkene 17 is followed by direct cyclisation at the ortho-position, or by spirodienyl formation followed by exclusive migration of the C-N bond.Such high regioselectivity has major advantages in the use of pyrrol-1-yl radicals as a synthetic route to unusual pyrrolo[1,2-a]quinolines.Scheme 8. FVP of the 2-styryl pyrrole 13.Reagents and conditions: (i) FVP, 750 °C.
Only low yields of products could be isolated from FVP of the 3-styryl isomer 15 at 750 °C, which suggests that the 3-substituted pyrrol-1-yl radical has no clear route to products (Scheme 9).The two compounds that were isolated in greatest amounts were the known 18 deaminated pyrrole 20 (11%) (c.f.Scheme 4) a product of hydrogen-capture by the pyrrol-1-yl radical and 8-methylpyrrolo[1,2-a]quinoline 19 (5%).The formation of 8methylpyrrolo[1,2-a]quinoline 19 requires rearrangement of the vinyl group from the 3-position to the 2position of the pyrrole, followed by cyclisation.Such 1,5-shifts are well-known in the thermal chemistry of pyrroles, 15 and although the rearrangement is not normally quantitative at temperatures as low as 750 C in our apparatus, they may well account for the formation of such a minor product (5%).

Scheme 10. Radical pathways resulting in equilibration and isomeric products.
The energy surface of the N-phenyliminyl corresponding to 1 (X = N) was modelled by DFT calculations (B3LYP/cc-pVDZ) (Figure 3). 19These show that the difference in barrier between the iminyl 1 (X = N) and the direct cyclisation intermediate 21 (X = N) and between the iminyl and the spirodienyl 3 (X = N) is 21.5 kJ mol -1 in favour of the direct cyclisation.The corresponding difference between the pyrrol-1-yl 2 (X = N), its direct cyclisation intermediate 22 (X = N) and the spirodienyl 3 (X = N) is 26.6 kJ mol -1 , again in favour of the direct cyclisation.This suggests that the direct cyclisation is relatively favoured kinetically in the case of the pyrrol-1yl, as found by experiment.Thermodynamically, the spirodienyl 3 (X = N) lies 40.6 kJ mol -1 above the direct cyclisation intermediate 21 [from the iminyl 1 (X = N)] and some 59.9 kJ mol -1 above the direct cyclisation intermediate 22 [from the pyrrol-1-yl 2 (X = N)].Again, direct cyclisation from the pyrrol-1-yl is relatively favoured thermodynamically, though it is somewhat surprising that the spirodienyl route can compete at all, given the high relative energies of its intermediate and transition states.By comparison, the difference in energy between the transition states relating the pyrrol-1-yl 2 (X = CH), its direct cyclisation intermediate 22 (X = CH) and the spirodienyl 3 (X = CH) is 55.6 kJ mol -1 , in favour of the direct cyclisation.Similarly, the energy of the spirodienyl 3 (X = CH) itself is some 72.9 kJ mol -1 higher than that of the direct cyclisation intermediate 21 (X = CH).The results of the calculations clearly suggest that only one isomer is formed by FVP of 12, because direct cyclisation of the pyrrol-1-yl takes place, rather than formation of the spirodienyl and exclusive migration of the C-N bond.Nevertheless, cleavage of the C-N bond in the spirodienyl 3 (X = CH), if formed, is indeed favoured over C-C cleavage by 31.8 kJ mol -1 .The very high energy of the vinyl radical 1 (X = CH) may help to explain why no precursor of such species under FVP conditions is known.
Finally, it is worth noting that pyrrol-1-yl radicals generated by homolysis of the N-N bond, are formed as -radicals 20 (e.g. 23) but intersystem crossing to the -surface to give -23 is likely to be facile. 6In practice the calculations show rather different electron density on the nitrogen in the 2 cases suggesting different character.Delocalisation of the -radical might promote some reactivity at the 3-position of species such as 2. In practice, whatever the electronic nature of the radical species involved, there is no doubt from the experimental results [including the very low yield of cyclisation product(s) by FVP of the 3-substituted precursor 15] that the pyrrolyl radical species behave as -radicals localised on the nitrogen atom.

Conclusions
We conclude that FVP reactions of 1-aminopyrrole derivatives provide useful routes to pyrrol-1-yl radicals, whose cyclisation chemistry is explored here for the first time.Cyclisation of 2-vinylpyrrol-1-yls proceeds regiospecifically to provide an unusual route to the pyrrolo[1,2-a]quinoline ring system.On the other hand, cyclisation of pyrrol-1-yls an arylimino chain takes place via spirodienyl radical formation and rearrangement, in competition with direct cyclisation.This result was confirmed by the cyclisation behaviour generation of an isomeric iminyl radical.Further reactions of azol-1-yl radicals will be reported in a subsequent paper.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded at 200 (or 250) and 50 (or 63) MHz respectively for solutions in [ 2 H]chloroform unless otherwise stated.Coupling constants are quoted in Hz.Mass spectra were recorded under electron impact conditions.